Obesity
Obesity is arguably the greatest public health threat in modem Western society, and it is an increasing threat throughout the world. A recent Surgeon General's report underscores the impact of obesity on human health. According to the report, approximately 61% of adults in the United States are overweight or obese, and the prevalence of overweight children and adolescents has doubled in the past two decades. The estimated economic burden of obesity to the United States alone is about $117 billion annually, and obesity is associated with an estimated 300,000 deaths per year. Further, numerous diseases have been correlated to obesity: Heart disease, certain types of cancer, sleep apnea, asthma, arthritis, pregnancy complications, depression and type II diabetes mellitus are all associated with excess weight.
In light of the health dangers attributed to obesity, many treatments, both pharmacological and non-pharmacological, have been developed to combat this enormous problem. Non-pharmacological approaches include diet, exercise and surgical intervention. While a well-balanced diet consumed in moderation coupled with regular physical activity is the most easily applied method of controlling or losing weight, the aforementioned facts indicate that this method has not reversed the trend towards increasing obesity. Reasons for lack of exercise may include cardiovascular problems or physical imparities that limit aerobic exercise, or lack of discipline, motivation, or time. Thus, behavior modification methods have proven unsuccessful in reversing the trend towards increasing obesity.
A variety of methods of treatment for obesity have been employed to address this pressing health issue. For instance, surgical intervention has been employed in conditions where obesity manifests as a real and immediate danger to a person's health. Previous surgical techniques to treat obesity included intragastric balloons and ileojejunal bypass surgery, but they often led to severe malnutrition, intestinal obstruction, and associated liver or renal failure. The art has progressed to biliopancreatic bypass, gastric bypass, and gastric partitioning (stomach-stapling) surgeries. While an improvement over older methods, these techniques are invasive surgical procedures with well-known and significant inherent risks and complications, and have not been in use long enough to be completely evaluated for long term safety.
Pharmacological methods to control weight have targeted a spectrum of physiological processes. Central nervous system (CNS) appetite suppressants interact with catecholaminergic receptors in the brain stem or regulate available serotonin levels. Drawbacks to these agents include possible addiction and numerous side effects including nervousness, insomnia, drowsiness, depression, nausea and lassitude.
Another class of pharmacologic agents for weight control promotes malabsorption of fats and carbohydrates through inhibition of digestive enzymes. Amylase, glycosidase and lipase inhibitors have been isolated from bacterial or fungal sources, and have been used to prevent the absorption of fats and carbohydrates in the digestive tract. A major problem with these agents is that it is virtually impossible to maintain physiological levels of these inhibitors that can effectively inhibit gastrointestinal enzymes, and therefore absorption. Additionally, the use of these inhibitors often leads to compensatory cravings for other foods. As an example, subjects taking a lipase inhibitor will often consume more carbohydrates to compensate for the loss of fat absorption in the diet, thereby negating any weight control benefits.
Another type of weight control agents is non-caloric, non-nutritive dietary substitutes, including saccharine, aspartame, and sucrose polyester (a fat substitute). The sucrose substitutes, saccharine and aspartame, have been linked to hyperphagia in order to compensate for the loss of calories from naturally occurring sucrose, and therefore may not help control weight. Furthermore, these are only sugar substitutes, and do not impact the role of fat consumed in the diet. Sucrose polyester is a sucrose bound to varying numbers and lengths of fatty acid chains. The size and complexity of the fatty acid chains prevent it from being absorbed, but also binds many fat-soluble vitamins, leading to vitamin deficiencies. Further, sucrose polyester has been associated with severe and unpredictable gastrointestinal instability and fecal incontinence.
In addition to the methods directed towards controlling obesity using pharmacological and surgical methods, a great deal of research has been conducted to elucidate the underlying genetic and biochemical mechanisms of obesity. Many human genes have been linked directly to obesity (Zhang et al., 1994, Nature 372:425-432; Deng et al., 2002, Am. J. Hum. Genet. 70:1138-1151), or to obesity susceptibility (Frougel and Boutin, 2001, Exp. Biol. Med. 226:991-996). Additionally, many of the genes involved in obesity have also been implicated in diabetes mellitus (Coleman et al., 1978, Diabetologia 14:141-148)
Diabetes Mellitus
Diabetes mellitus is a devastating metabolic disease characterized by the presence of chronically elevated blood glucose, abnormal glucose, protein, and lipid metabolism due to either insulin deficiency or resistance. The World Health Organization classifies patients as either having insulin-dependent diabetes mellitus (Type I, IDDM) or non-insulin-dependent diabetes mellitus (Type II, NIDDM). Type I patients do not produce sufficient amounts of insulin to maintain normal glucose metabolism. Type II patients exhibit various degrees of insulin resistance and typically have increased insulin levels early in the disease. Insulin levels may decrease as pancreatic secretion falls, presumably because of chronic over-stimulation.
Diabetes affects over 14 million in the United States (90% Type II and 10% type I) and accounts for approximately 15% of all health care expenditure. It is the leading cause of adult blindness in people 20 to 74 years old, of non-traumatic lower extremity amputation, and of end-stage renal disease. Since the hallmark of type I diabetes is insulin deficiency, patients are treated with insulin. In contrast, patients with Type II diabetes frequently do not require exogenous insulin, since insulin production is often adequate. Instead, treatment of Type II diabetes usually begins with diet and lifestyle modifications. If after an adequate trial of diet and lifestyle modifications, fasting hyperglycemia persists, then an oral hypoglycemic agent is used. Finally, insulin may be added if adequate glucose control cannot be achieved with oral agents.
There are two broad classes of oral hypoglycemic agents. Sulfonylureas inhibit ATP-regulated potassium channels present in the pancreatic β cells and facilitate endogenous insulin secretion. The second class of agent, exemplified by rosiglitazone, ameliorates insulin resistance. They are believed to be preferable to sulfonylureas since they specifically reverse an essential feature of Type II diabetes i.e. insulin resistance. Drugs that improve insulin sensitivity have great potential for use in the treatment of Type II diabetes.
Kv1.3
Of the genes implicated in obesity susceptibility, a few are involved in insulin related signaling, especially in the central nervous and endocrine systems. Knockout mice lacking the neuronal insulin receptor (JR) exhibited normal neuronal survival and brain development, but developed mild insulin resistance, diet-sensitive obesity, and weighed approximately 15% more than controls (Bruning et al., 2000, Science 289:2122-2125), suggesting a role for insulin in the CNS and a role for CNS insulin in obesity. The downstream signaling pathway initiated by the insulin-IR interaction remains ill defined, but proteins containing Src-homology-3 and Src-homology domains, as well as the voltage-gated potassium channel protein Kv1.3, have been implicated as insulin receptor substrates (Fadool et al., 2000, J. Neurophysiol. 83:2332-2348).
Kv1.3 belongs to the Shaker family of voltage regulate potassium channels. Kv1.3 is expressed in the central nervous system, kidney, lymphocytes, liver, testis, spermatozoa, osteoclasts, heart and skeletal muscle (Yao et al, 1996, J. Clin. Invest. 97:2525-2533; Cahalan et al., 1991, Curr. Topics. Memb. 39:357-394; Ghanshani et al., 2000, J. Biol. Chem. 275;37137-37149; Levite et al., 2000, J. Exp. Med. 191:1167-1176; Mourre et al., 1999, J. Pharmacol. Exp. Ther. 291:943-952; Jacob et al., 2000, Mol. Hum. Reprod. 6:303-313, Arkett et al., 1994, Receptors Channels 2:281-293; Komarova et al., 2001, Curr. Pharm. Des. 7:637-654). Analysis of the primary amino acid sequence of Kv1.3 revealed that the protein contains six-transmembrane domains, a consensus protein kinase C site, a tyrosine kinase phosphorylation site, and a glycosylation site. The protein kinase C site is conserved amongst all Shaker potassium channels, and phosphorylation of that site appears to down regulate potassium channel activity (Chandy et al., 1995, In: Handbook of Receptors and Channels, C.R.C. Press, Inc., Boca Raton, Fla.). Recent data has also suggested that Kv1.3 activity is downregulated by tyrosine phosphorylation through the action of insulin (Fadool et al., 2000, J. Neurophysiol. 83:2332-2348).
Many studies have concluded that Kv1.3 is important in thymocyte activity (DeCoursey et al., 1985, J. Neuroimmunol. 10:71-95; Matteson and Deutch, 1984, Nature 307:468-471). Additionally, it has been reported that inhibition of Kv1.3 channels with selective toxins (correolide, margatoxin, and derivatives) has an immunosuppressive function (Koo et al., 1999, Cell Immunol. 197:99-107). Finally, inhibition of Kv1.3 with margatoxin or similar compounds has been shown to ameliorate experimental autoimmune encephalomyelitis, a model for multiple sclerosis, by suppressing the T-cell response to myelin basic protein (Beeton et al., 2001, Proc. Nat. Acad. Sci. USA 98:13942-13947); inhibition of Kv1.3 in rats increases associative learning and memory (Kourrich et al., 2001, Behav. Brain Res. 120:35-46). However, the physiological role of Kv1.3 in the CNS and other physiological processes remains poorly defined.
Despite the current status of obesity and obesity-associated disease as a world-wide crisis, there are no effective and sustainable treatments for this disease. The treatment of diabetes still requires further refinement, especially the discovery of drugs that increase insulin sensitivity. Therefore, there is a long felt need for a safe and effective method to treat obesity and associated disorders, such as diabetes. The present invention meets this need.